ABOUT THE DIABETIC COMPLICATIONS CONSORTIUM (DiaComp):

The goal of the NIDDK-sponsored Diabetic Complications Consortium (DiaComp) is to advance the study of diabetic complications and promote communication
and collaboration between investigators involved in complications research by supporting scientific meetings and funding new research activities.

DiaComp Pilot and Feasibility Program

This program solicits and funds small Pilot and Feasibility (P&F) projects in high-impact areas of diabetic complications research that fall
within the primary mission of the NIDDK (please see the
NIDDK website for full details). NIDDK complications include diabetic nephropathy, uropathy, neuropathy, neurocognition, gastrointestinal, liver, bone, and wound
healing. Applications focused on all other diabetic complications (including diabetic retinopathy and cardiovascular disease) do NOT fall within the primary mission of
the NIDDK and will be deemed non-responsive. If an application proposes to study multiple diabetic complications, a majority of the proposal must address an NIDDK
complication of primary interest.

This program aims to support discovery (hypothesis generating) and innovative (high-risk/high-reward) research that will advance our understanding of diabetic
complications and that are increasingly difficult to support through standard NIH mechanisms. Basic, translational and clinical research proposals are
encouraged. When appropriate, the use of human samples is strongly encouraged. Research involving human subjects is limited to observational studies with
non-invasive or minimally invasive testing and must have IRB approval that includes the collection and use of human samples for research purposes. Clinical trials,
as defined by the NIH, are beyond the scope of this program. For further details and resources to help clarify the NIH definition, please consult information
posted at the NIH Clinical Trials website (
https://grants.nih.gov/policy/clinical-trials/definition.htm ). Diabetic complications manifest themselves differently between men and women. Understanding
the molecular underpinnings of these manifestations is critical to designing tailored therapeutic approaches.

Awards are expected to prepare the applicant(s) to submit a future investigator-initiated project (e.g. NIH R01). Lower priority will be given to applicants
who have received DiaComp support in the past three years. Foreign applications are NOT allowed.

Applications of 5 pages requesting up to $100,000 for one year are due June 11, 2018.

Current areas of emphasis include, but are not limited to:

New Areas of Interest for 2017 are coming soon.

Human Tissue Interrogation
Develop and use innovative technologies to analyze human tissue from end organs of diabetic complications to better understand (patho)physiology and (dys)function.
For example:

Develop new protocols, tools or reagents for the molecular/omic interrogation of healthy or diseased human tissue. These
may involve imaging methods at the single cell level (e.g., SWITCH, systems-wide control of interaction time and kinetics of
chemicals, CyTOF mass cytometry, CLARITY, etc.) or digestion of specimens into single cells for further analysis (e.g, flow cytometry,
microfluidics, mass cytometry or chemical cytometry).

Profile and validate cell types isolated from healthy or diseased human tissue using FACS, laser-capture or other approaches. Molecular/omic
profiling of cell types should inform in vitro and in vivo efforts to model, recreate or regenerate these cell types to study human (patho)physiology
and (dys)function.

Assess the quality of human bone in diabetes. Increased fracture risk is an important morbidity in subjects with T2DM. Bone imaging
technologies, have shown differences in bone quality and bone marrow fat content as compared to non-diabetic individuals. The role of
advanced glycation end-product (AGE) accumulation has also been implicated in this increased fracture risk. This information has
increased our understanding of how T2DM adversely impacts both bone metabolism and fracture risk, but the histological characterization
of skeletal abnormalities in T2DM has been poorly explored. This information may provide important insights that may lead to a better
understanding of this complication as well provide insights on how to ameliorate it.

Examine the localized tissue secretory and cellular microenvironments (e.g., extracellular matrix, interstitium, wound exudate) using emerging technologies
such as nanoFACS for extracellular vesicle profiling, CLASI-FISH for exploring the 3D relationships in the microbiome, or MALDI-based technologies to
characterize the extracellular proteome as it relates to the development or extent of diabetic complications.

Bioengineered Models
Recent advances in engineering, developmental biology, and genome editing have stimulated development of “tissue chip” and “organoid” models of
numerous tissue compartments and disease states. The 3D cell culture in vitro models generated using human cells and physiologic conditions
(e.g. flow) have the potential to more accurately recapitulate human phenotypes.
For example:

Develop tissue chip models of end organs affected by diabetic complications, including components that may be affected by diabetic complications (e.g., microvasculature or innervation).

Use human cells to develop mature organoid models of end organs affected by diabetic complications. Develop methods to support the maturation of organoids.

Study mechanisms of diabetic complications using a tissue chip model of an affected end organ.

Evaluate a therapeutic strategy for diabetic complications using an assay involving an organoid model.

Repair and Regeneration
Devise strategies to stimulate repair/regeneration and restore function in end organs affected by diabetic complications.
For example:

Identify and interrogate endogenous repair and regeneration pathways. Screen for ways to promote endogenous repair and regeneration in vivo.

Define repair circuits to identify drug targets that will enhance repair and develop target-based small screening assays. Use phenotype screening
assays to identify small molecules that will stimulate repair/regeneration and restore failing function.

Biosensors
The pathogenesis of diabetic complications is metabolically and genetically complex and involves multiple organ systems. Model organisms are well suited for
studying pathophysiology driven or impacted by tissue- and organ-crosstalk. The transparency of C. elegans and zebrafish
larvae permits the facile monitoring of cell-based biosensors designed to measure inter- and intra-cellular processes in free living organisms. With the advent
of improved genome-editing technologies and large-scale efforts to develop biosensors (e.g. ER stress, oxidative stress, autophagy, glucose levels, hormone levels,
albuminuria, etc.), the time is right for researchers to develop novel tools and adapt existing approaches to advance our understanding of the mechanisms
underlying diabetic complications.
For example:

Develop non-mammalian models organism lines and protocols to study the effects of altered glucose homeostasis on the central and peripheral
nervous systems leading to further disruption of metabolic control and complications such as neuropathic pain, gastroparesis, and disturbed renal function.

Develop non-mammalian model organism assays, reporters, or other tools to identify novel or understudied processes that impact the
molecular anatomy and physiology of kidney and urinary tract development, function or dysfunction in response to long-term dysglycemia.

Develop assays of mucosal immune, gut barrier, and other intestinal functions which could be used to elucidate functional consequences of
human mutations conferring diabetic complications risk.

Develop reporter lines to track development of fibrosis in liver, kidney and other end organs of diabetic complications.

Each proposal should indicate how these next generation tools, lines and protocols will be broadly shared.

Pre-clinical Testing
There is a compelling need to translate novel, scientifically meritorious therapeutic interventions for diabetic complications.
For example:

Support the preclinical work necessary to obtain "proof of principle" establishing that a new molecule or novel approach will be a viable candidate
for expanded clinical evaluation.

Pilot studies to support the development and use of novel cell-based, organoid, or in vivo assays for the discovery and preclinical testing of
potential therapies for diabetic complications.

Additional preclinical testing is often required to validate potential therapies under disease-specific conditions and in multiple systems before
they can progress along the drug development pipeline.

Bioengineer healthy and diseased end organs of diabetic complications, including incorporation of appropriate cell types, for functional testing and screening.

Budget requests should be commensurate with project needs over a one year project period. While average DiaComp P&F awards are $60,000 Total Costs for one year, well
justified requests for support of up to $100,000 Total Costs per year will be considered.

When appropriate, the use of human samples is strongly encouraged, including the linking of human samples to existing tissue repositories and databases (e.g. the
NIDDK repository [www.niddkrepository.org/home/] or dkNET [http://www.dknet.org/]). Research involving human subjects is limited to observational studies with non-invasive or minimally invasive testing and
must have IRB approval that includes the collection and use of human samples for research purposes. Interventional clinical trials are beyond the scope of this program.

Streptozotocin (STZ) is used by DiaComp members to induce diabetes in a number of the animal models developed by the consortium. STZ is toxic to the insulin-producing
beta cells of the pancreas and used to induce diabetes similar to a type I diabetic patient. Some reports suggest cellular toxicity outside of the pancreas. STZ also
exhibits broad spectrum antibacterial properties and may alter the gut microbiota. Applicants to DiaComp are reminded to justify their choice of approaches and models of
diabetes, including the STZ model, to ensure that appropriate controls are included in all studies and to consider use of complementary approaches. Reviewers are asked to
accept use of appropriately justified STZ-diabetes models with appropriate controls unless they can provide direct evidence that the model is inappropriate for the
proposed studies.

Applications are due June 11, 2018 for October start dates.

Applications of 5 pages requesting up to $100,000 for one year are due June 11, 2018.

Current areas of emphasis include, but are not limited to:

New Areas of Interest for 2017 are coming soon.

Human Tissue Interrogation
Develop and use innovative technologies to analyze human tissue from end organs of diabetic complications.
For example:

Develop new protocols, tools or reagents for the molecular/omic interrogation of healthy or diseased human tissue. These
may involve imaging methods at the single cell level (e.g., SWITCH, systems-wide control of interaction time and kinetics of
chemicals, CyTOF mass cytometry, CLARITY, etc.) or digestion of specimens into single cells for further analysis (e.g, flow cytometry,
microfluidics, mass cytometry or chemical cytometry).

Profile and validate cell types isolated from healthy or diseased human tissue using FACS, laser-capture or other approaches. Molecular/omic
profiling of cell types should inform in vitro and in vivo efforts to model, recreate or regenerate these cell types.

Examine the localized tissue secretory and cellular microenvironments (e.g., extracellular matrix, interstitium, wound exudate) using emerging
technologies such as nanoFACS for extracellular vesicle profiling, CLASI-FISH for exploring the 3D relationships in the microbiome, or MALDI-based
technologies to characterize the extracellular proteome as it relates to the development or extent of diabetic complications.

Bioengineer healthy or diseased end organs of diabetic complications, including incorporation of appropriate cell types, for functional testing and screening.

Biosensors
The pathogenesis of diabetic complications is metabolically and genetically complex and involves multiple organ systems. Model
organisms are well suited for studying pathophysiology driven or impacted by tissue- and organ-crosstalk. The transparency of C.
elegans and zebrafish larvae permits the facile monitoring of cell-based biosensors designed to measure inter- and intra-cellular
processes in free living organisms. With the advent of improved genome-editing technologies and large-scale efforts to develop
biosensors (e.g. ER stress, oxidative stress, autophagy, glucose levels, hormone levels, albuminuria, etc.), the time is right
for researchers to develop novel tools and adapt existing approaches to advance our understanding of the mechanisms underlying
diabetic complications.
For example:

Develop non-mammalian models organism lines and protocols to study the effects of altered glucose homeostasis on the central and
peripheral nervous systems leading to further disruption of metabolic control and complications such as neuropathic pain,
gastroparesis, and disturbed renal or cardiac function.

Develop non-mammalian model organism assays, reporters, or other tools to identify novel or understudied processes that impact the
molecular anatomy and physiology of kidney and urinary tract development, function or dysfunction in response to long-term dysglycemia.

Develop assays of mucosal immune, gut barrier, and other intestinal functions which could be used to elucidate functional consequences of
human mutations conferring diabetic complications risk.

Develop reporter lines to track development of fibrosis in liver, kidney and other end organs of diabetic complications.

Each proposal should indicate how these next generation tools, lines and protocols will be broadly shared.

Biofilms
Biofilms lack a precise definition but are generally accepted to be structured communities of microorganisms, adhered to a surface, and exhibiting phenotypic
heterogeneity. Compared to planktonic (free-floating) bacteria, biofilm bacteria are more virulent and resistant to treatment and host immune factors. Biofilms
are under-appreciated as a contributor to diabetic complications.
For example:

Biofilms can be monolayer or multilayer and contain heterogeneous or homogenous populations of microorganisms associated with biotic and abiotic
surfaces. Biofilm formation by pathogenic bacteria contribute significantly to antibiotic resistance and infection recurrence. Host-pathogen
interaction, extracellular matrix formation, and quorum sensing are involved in the formation of biofilms but little is known about how these processes
are affected by changes in tissue and cellular physiology in the context of chronic diabetes. Such changes may contribute to diabetic complications such as
recurrent urinary tract infections, bladder dysfunction and prostatitis.

It has become increasingly apparent that the urine is not a “sterile” environment. Recent data indicate the bladder and urine are hosts to a rich array of
micro-organisms that are likely to play important roles in maintaining normal bladder function. We encourage pilot proposals exploring how these “native”
micro-organisms interact with the pathogenic micro-organisms to promote or prevent biofilm formation and recurrent UTIs within the context of diabetes.

Artificial surfaces commonly used for in-dwelling urinary catheters are a recognized substrate for biofilm formation and the unique milieu of diabetes may
alter the population of micro-organisms present in the urinary bladder to promote biofilm formation. Specific topics of interest include elucidating the
interaction of pathogenic micro-organisms with catheter materials and the exploration of alternative materials that preclude pathogenic biofilm formation in
diabetic patients.

The twenty-week healing rate for neuropathic diabetic foot ulcers is about 50% and bacterial biofilms are a major cause for the failure of chronic wounds to
heal. Detection of biofilms is critical for diagnosis, but standard culture methods and other indicators such as visual and olfactory examination of wounds
are inadequate. The treatment of diabetic foot ulcers requires a better understanding of the mechanisms by which certain bacteria within the complex flora
of a diabetic wound and within biofilms become pathogenic. New molecular microbiological technologies have the potential to detect bacterial biofilms and their
role in the chronicity of diabetic foot ulcers. Specific topics of interest are the discovery and study of novel pathogenic mechanisms of biofilms for diabetic wound
healing and the development of detection methods for biofilms in diabetic wounds for use in research and the clinic.

Insulin resistance and type 2 diabetes impacts neurocognitive function via mechanisms independent from those typically associated with Alzheimer’s Disease
pathology. In addition, there is a growing appreciation that type 1 diabetes may be associated with neurocognitive dysfunction. Understanding the mechanism(s)
that explain the neurocognitive complications of insulin resistance and diabetes (both type 1 and type 2) will be important if we are going to develop novel
therapeutic targets and approaches. Moreover, an acute clinically important feed-forward downward spiral can develop because even mild neurocognitive impairment
can prevent impaired persons with diabetes from managing his/her anti-diabetic medications. Thus, there are important individual, societal, and economic
implications.
Metabolic disease may impact the brain in ways that differ from its effects on other end organs of diabetic complications. It is possible that due to aging
and disease-related factors, isolating mechanisms may be more complex and clinical targets less modifiable as individuals advance in age and disease burden
increases. Therefore, there will be a special emphasis on research that addresses potential mechanisms that may be independent of those associated with aging
or complex disease.

Development, translation, and/or validation of imaging or other methods to measure the neuropathophysiologic changes associated with diabetes.

Elucidating mechanisms for how diabetes may impact the brain in ways that differ from its effects on other end organs.

Effect of neuropathology and brain dysfunction on peripheral metabolism and diabetes.

Clinicopathological correlation as well as cause-and-effect research designs aimed at identifying the sequence(s) of events that can lead to the
development of specific neural systems and cognitive functions impacted by diabetes and its other complications, especially disruptions with the
great impact on clinical care.

Approaches that take advantage of recent breakthroughs in the genetics of diabetes and insulin resistance are encouraged, as are computational approaches
applied to multi-omics brain data from persons with diabetes.

We have an interest in both human and non-human animal research. However, the animal model and the mechanisms tested need to be well-justified in their
translational potential to humans.

Pre-clinical Testing
There is a compelling need to translate novel, scientifically meritorious therapeutic interventions for diabetic complications.
For example:

Support the preclinical work necessary to obtain "proof of principle" establishing that a new molecule or novel approach will be a viable candidate
for expanded clinical evaluation.

Pilot studies to support the development and use of novel cell-based, organoid, or in vivo assays for the discovery and preclinical testing of
potential therapies for diabetic complications.

Additional preclinical testing is often required to validate potential therapies under disease-specific conditions and in multiple systems before
they can progress along the drug development pipeline.

Bioengineer healthy and diseased end organs of diabetic complications, including incorporation of appropriate cell types, for functional testing and screening.

Budget requests should be commensurate with project needs over a one year project period. While average DiaComp P&F awards are $60,000 Total Costs for one year, well
justified requests for support of up to $100,000 Total Costs per year will be considered.

When appropriate, the use of human samples is strongly encouraged, including the linking of human samples to existing tissue repositories and databases (e.g. the
NIDDK repository [www.niddkrepository.org/home/] or dkNET [http://www.dknet.org/]). Research involving human subjects is limited to observational studies with non-invasive or minimally invasive
testing and must have IRB approval that includes the collection and use of human samples for research purposes.

Interventional clinical trials are beyond the scope of this program.

Streptozotocin (STZ) is used by DiaComp members to induce diabetes in a number of the animal models developed by the consortium. STZ is toxic to the insulin-producing
beta cells of the pancreas and used to induce diabetes similar to a type I diabetic patient. Some reports suggest cellular toxicity outside of the pancreas. STZ also
exhibits broad spectrum antibacterial properties and alters the gut microbiota. Applicants to DiaComp are reminded to justify their choice of approaches and models of
diabetes, including the STZ model, to ensure that appropriate controls are included in all studies and to consider use of complementary approaches. Reviewers are asked to
accept use of appropriately justified STZ-diabetes models with appropriate controls unless they can provide direct evidence that the model is inappropriate for the
proposed studies.

Applications are due June 11, 2018 for October start dates.

Applications of 5 pages requesting up to $100,000 for one year are due June 11, 2018.

Current areas of emphasis include, but are not limited to:

1. Non-mammalian Organisms
The pathogenesis of diabetic complications is metabolically and genetically complex and involves multiple organ
systems. Drosophila, zebrafish, and C. elegans are genetically tractable organisms that are well suited and
powerful for modeling pathophysiology driven or impacted by tissue- and organ-crosstalk. The transparency of
C. elegans and zebrafish larvae permits the facile monitoring of cell-based biosensors designed to measure inter-
and intra-cellular processes in free living organisms. With the advent of improved genome-editing technologies
and large-scale efforts to develop biosensors (e.g. ER stress, oxidative stress, autophagy, glucose levels, hormone
levels, albuminuria, etc.), the time is right for researchers to develop novel tools and adapt existing approaches
to advance our understanding of the mechanisms underlying diabetic complications.
For example:

Develop non-mammalian model organism lines that a) mimic aspects of the human pathology of diabetic
complications through protocols that induce diabetes and b) express cell-based physiologically-relevant
biosensors and reporters to simultaneously image/measure physiologic processes in real-time to explore
the sequence of inter- and intra-cellular events leading to cellular dysfunction, disturbed physiological
processes, and end-organ damage.

Develop non-mammalian models organism lines and protocols to study the effects of altered glucose homeostasis
on the central and peripheral nervous systems leading to further disruption of metabolic control and complications
such as neuropathic pain, gastroparesis, and disturbed cardiac function.

Develop non-mammalian model organism assays, reporters, or other tools to identify novel or understudied processes
that impact the molecular anatomy and physiology of kidney and urinary tract development, function or dysfunction in
response to long term dysglycemia.

Develop assays of mucosal immune, gut barrier, and other intestinal functions which could be used to elucidate functional
consequences of human mutations conferring diabetic complications risk.

Develop reporter lines to track development of fibrosis in liver, kidney, adipose tissue and other end organs of diabetic
complications.

Each proposal should indicate how these next generation tools, lines and protocols will be broadly shared.

2. Mitochondria: Beyond OxPhos
Ongoing investigation into the pathogenesis of multiple diseases has revealed non-traditional and
unexpected roles for mitochondria in the regulation of cell and tissue homeostasis.
For example:

Sustaining a healthy population of mitochondria requires the addition of new functional mitochondria and removal of
old dysfunctional mitochondria. In addition to de novo biogenesis, circulating stem cells have been shown to share
their functional mitochondria with injured cells (including hepatocytes, lung epithelia, and hematopoietic stem cells)
to mitigate tissue damage. Conversely, recent evidence suggests that retinal neurons can package their dysfunctional
mitochondria and expel them to neighboring astrocytes for degradation (transmitophagy).

Mitochondrial bioenergetics has been implicated in a broad spectrum of metabolic and degenerative diseases. A new
class of drugs targeting cardiolipin is believed to improve mitochondrial “plasticity” and is being tested in diabetes,
heart failure, ischemic injury, neurodegeneration, retinal and skin diseases, and chronic kidney disease.

Adult stem cells remain metabolically inactive until triggered to proliferate and replenish a tissue. Recent work suggests
that the mitochondrial unfolded protein response is coupled to cellular metabolism and regulates stem cell aging. In hematopoietic
stem cells, for example, it appears that aging is not due to passive accumulation of cellular damage over time, but rather an active
repression of protective pathways and suggests that targeting these protective pathways in mitochondria could reverse aging and
restore tissue homeostasis.

In parallel to these new scientific discoveries, emerging technologies (e.g. real-time imaging) and analytical tools (e.g. omics) are
poised to facilitate the investigation of novel and unexpected roles of mitochondria in diabetic complications. Successful applications
will discover previously unknown targets and pathways, test innovative hypotheses, and/or employ state-of-the-art technologies directed
at advancing our understanding of mitochondria in the development and treatment of diabetic complications.

3. Biofilms
Biofilms lack a precise definition but are generally accepted to be structured communities of microorganisms, adhered to a surface, and exhibiting
phenotypic heterogeneity. Compared to planktonic (free-floating) bacteria, biofilm bacteria are more virulent and resistant to treatment and host
immune factors. Biofilms are under-appreciated as a contributor to diabetic complications.
For example:

Diabetic foot ulcers are a common complication of diabetes with a lifetime prevalence of about 25%. The twenty week healing rate for neuropathic
diabetic foot ulcers is about 50% and bacterial biofilms are a major cause for the failure of chronic wounds to heal. Detection of biofilms is
critical for diagnosis, but standard culture methods and other indicators such as visual and olfactory examination of wounds are inadequate.
The treatment of diabetic foot ulcers requires a better understanding of the mechanisms by which certain bacteria within the complex flora of a
diabetic wound and within biofilms become pathogenic. New molecular microbiological technologies have the potential to detect bacterial biofilms
and their role in the chronicity of diabetic foot ulcers. Specific topics of interest are the discovery and study of novel pathogenic mechanisms
of biofilms for diabetic wound healing and the development of detection methods for biofilms in diabetic wounds for use in research and the clinic.

Biofilms can be monolayer or multilayer and contain heterogeneous or homogenous populations of microorganisms associated with biotic and abiotic
surfaces. Biofilm formation by pathogenic bacteria contribute significantly to antibiotic resistance and infection recurrence. Host-pathogen
interaction, extracellular matrix formation quorum sensing are involved in the formation of biofilms but little is known about how these processes
are affected by changes in tissue and cellular physiology due to diabetes. Such changes may contribute to diabetic complications such as recurrent
urinary tract infections and bladder dysfunction.

4. Hormones and Gender
Diabetes disrupts normal energy homeostasis and has the potential to alter steroid-hormone responsiveness. As males and females differ in their complement
of estrogen-responsive and androgen-responsive tissues, they may suffer different tissue complications as a result of diabetes.
For example:

A recent meta-analysis of T1DM observational studies suggests that, compared to nondiabetic individuals, women with Type 1 diabetes have twice the
excess risk of fatal and non-fatal cardiovascular events than men with Type 1. Similar evidence supports the same in women with Type 2. The biological
mechanisms underlying this difference are unclear.

Men with increased adiposity and Type 2 diabetes have lower testosterone levels and higher circulating estrogens due to somatic aromatase activity.
These levels of estrogen can predispose men to urologic complications. Few studies have examined these differences mechanistically, but estrogen
signaling through both genomic and non-genomic receptors appears to play a role.

To better understand the interplay between steroid hormones and the development of sex-specific diabetic complications, we are interested in pilot
projects that discover or interrogate new mechanisms. Successful applications will leverage appropriate models systems or human tissue to address novel
research questions, with a focus on diabetic complications.

5. Neurocognition
Emerging data has established a link between diabetes and neurocognitive dysfunction, including dementia. Understanding the mechanism(s) that explain
the neurocognitive complications of diabetes will be important if we are going to be successful in developing therapeutic targets and approaches to
mitigate the effects of metabolic disease on the brain and cognitive function. For example:

Metabolic disease may impact the brain in ways that differ from its effects on other end organs. It is possible that due to aging and disease-related
factors, isolating mechanisms may be more complex and clinical targets less modifiable as individuals advance in age and disease burden increases. Therefore,
there will be a special emphasis on research that addresses potential mechanisms that may be independent of those associated with aging or complex disease or
how diabetes-specific pathology may interact with aging and complex disease-related processes (e.g. other severe complications of diabetes, CVD, dementia).

The shared pathophysiology of diabetes and dementia, including vascular and Alzheimer’s disease pathology (e.g. Aβ, tau).

Pathophysiology unique to diabetes (e.g. glycemia, insulin) and the impact on cognition and dementia.

The effect of neuropathology and brain dysfunction on peripheral metabolism and diabetes.

We have an interest in both human and non-human animal research. However, the animal model and the mechanisms tested need to be well-justified in their
translational potential to humans.

6. Pre-clinical Testing
There is a compelling need to translate novel, scientifically meritorious therapeutic interventions for diabetic complications.
For example:

Support the preclinical work necessary to obtain "proof of principle" establishing that a new molecule or novel approach will be a viable candidate
for expanded clinical evaluation.

Pilot studies to support the development and use of novel cell-based, organoid, or in vivo assays for the discovery and preclinical testing of
potential therapies for diabetic complications.

Additional preclinical testing is often required to validate potential therapies under disease-specific conditions and in multiple systems before
they can progress along the drug development pipeline.

When appropriate, the use of human samples is strongly encouraged, including the linking of human samples to existing tissue repositories and databases (e.g. the
NIDDK repository [www.niddkrepository.org/home/] or dkNET [http://www.dknet.org/]). Research involving human subjects is limited to observational studies with non-invasive or minimally invasive
testing and must have IRB approval that includes the collection and use of human samples for research purposes.

Interventional clinical trials are beyond the scope of this program.

International institutions and organizations are eligible for support.

Applications are due June 11, 2018 for October start dates.

Applications of 5 pages requesting up to $100,000 for one year are due May 8th, 2015.

Current areas of interest include, but are not limited to:

Interrogation of human samples or resources with genetics, epigenetics, and/or systems biology. Use of human tissue to identify different molecular
and anatomic “subtypes” of end-organ disease, including potential differences between T1D and T2D. Linking and coordination of human samples to
existing tissue repositories and databases.

Application of stem cells, including induced pluripotent stem (iPS) cells, and regenerative therapies to the repair and reversal of diabetic
complications. The development of stem cell based models of disease, including 3D tissue organoids.

Use of relevant model systems to accelerate gene X environment (GEI) studies. Pilot studies to assess the role of the microbiome or virome in diabetic
complications. Investigation of mechanisms for the possible role of metals in the development of complications and chelation therapy in the prevention or
reversal of complications.

Pilot studies to support the development and use of novel cell-based, organoid, or in vivo assays for the discovery and preclinical testing of potential
therapies for diabetic complications.

Budget requests should be commensurate with project needs over a one year project period. While average DiaComp P&F awards are
$60,000 Total Costs for one year, well justified requests for support of up to $100,000 Total Costs per
year will be considered.

International institutions and organizations are eligible for support.

Applications are due May 8th, 2015 for September start dates.

Applications of 5 pages requesting up to $100,000 for one year are due Friday, May 16, 2014.

Current areas of interest include, but are not limited to:

Use of human tissue to better define the histo-pathology and -morphometry of organs affected by systemic diabetes.

Budget requests should be commensurate with project needs over a one year project period. While average DiaComp P&F awards are
$60,000 Total Costs for one year, well justified requests for support of up to $100,000 Total Costs per
year will be considered.

International institutions and organizations are eligible for support.

Applications are due Friday, May 16, 2014 for September start dates.

Applications of 5 pages requesting up to $100,000 for one year are due Friday, May 17, 2013.

Budget requests should be commensurate with project needs over a one year project period. While average DiaComp P&F awards are
$60,000 Total Costs for one year, well justified requests for support of up to $100,000 Total Costs per
year will be considered.

International institutions and organizations are eligible for support.

Applications are due Friday, May 17, 2013 for September start dates.

Applications of 5 pages requesting up to $100,000 for one year are due Thursday, May 17, 2012.

Use of human tissue to better define the histo-pathology and -morphometry of organs affected by systemic
diabetes. Use human tissue to identify different molecular and anatomic “subtypes” of end-organ disease.

Application of stem cells, including induced pluripotent stem (iPS) cells, and regenerative therapies to
the repair and reversal of diabetic complications.

Budget requests should be commensurate with project needs over a one year project period. While average DiaComp P&F awards are
$60,000 Total Costs for one year, well justified requests for support of up to $100,000 Total Costs per
year will be considered.

International institutions and organizations are eligible for support.

Applications are due Thursday, May 17th, 2012 for September start dates.

Applications of 5 pages requesting up to $100,000 for one year are due Tuesday, May 17th, 2011.

Current areas of interest include, but are not limited to:

Application of stem cells, including induced pluripotent stem (iPS) cells and regenerative therapies
to the repair and reversal of diabetic complications.

Expanded in vivo efficacy studies for preclinical validation of promising new therapeutics for diabetic
complications.

Budget requests should be commensurate with project needs over a one year project period. While average DiaComp P&F awards are
$60,000 Total Costs for one year, well justified requests for support of up to $100,000 Total Costs per
year will be considered.

International institutions and organizations are eligible for support.

Applications are due Tuesday, May 17th, 2011 for September start dates.

Applications of 5 pages requesting up to $100,000 for one year are due Monday, May 3rd, 2010.

Current areas of interest include, but are not limited to:

Generation and characterization of stem cell populations, including pluripotent or tissue-specific stem cells, or human and mouse iPS, to support preclinical studies of therapeutic efficacy in animal models of diabetic complications;

Examination of regenerative and repair functions of endogenous cell populations in animal models of diabetes and its complications;

Evaluation of the impact of diabetes and its complications on stem cell production, function and recruitment to cellular niches at sites of end-organ injury;

Development of mouse models with humanized cell populations or organ
systems suitable for use in complications research (eg, mice with human
endothelium, skin, cardiac, kidney, nervous or urologic tissue);

Production and validation of immunodeficient mouse models to serve as recipients
for transfer of human cell populations to assay or impact diabetic complications;

Validation of phenotyping assays to measure efficacy of cell-based therapies for diabetic complications.

Budget requests should be commensurate with project needs over a one year project period. While average DiaComp P&F awards are
$60,000 Total Costs for one year, well justified requests for support of up to $100,000 Total Costs per
year will be considered.

International institutions and organizations are eligible for support.

Applications are due Monday, May 3rd, 2010 for September start dates.

Applications of 5 pages requesting up to $100,000 for one year are due Friday, May 1st, 2009.

Models and studies to assess role of inflammation, particularly inflammatory lipid signaling in complications development

Development of clinically relevant endpoints in animal models of diabetic retinopathy, neuropathy and uropathy

Projects designed to test the role of diet, aging or environmental/enteric bacteria in modulating complication phenotype

Studies of the microbiome and its ability to modulate the severity of diabetic complications in relevant animals models

Budget requests should be commensurate with project needs over a one year project period. While average DiaComp P&F awards are
$60,000 Total Costs for one year, well justified requests for support of up to $100,000 Total Costs per
year will be considered.

International institutions and organizations are eligible for support.

Applications are due Friday, May 1st, 2009 for September start dates.

Applications of 5 pages requesting up to $100,000 for one year are due May 1st, 2008.

Current areas of interest include, but are not limited to:

Develop new technologies or miniaturization of existing technologies for use in
mice,

Establish new types of mathematical models, informatics, databases or products
that augment the mission of the center.

Budget requests should be commensurate with project needs over a one year project period. While average DiaComp P&F awards are
$60,000 Total Costs for one year, well justified requests for support of up to $100,000 Total Costs per
year will be considered.

International institutions and organizations are eligible for support.

Applications are due Thursday May 1st, 2008 for September start dates.

Applications of 5 pages requesting up to $100,000 for one year are due Tuesday, May 1st, 2007.

Current areas of interest include, but are not limited to:

Develop new technologies or miniaturization of existing technologies for use in
mice,

Establish new types of mathematical models, informatics, databases or products
that augment the mission of the center.

Budget requests should be commensurate with project needs over a one year project period. While average DiaComp P&F awards are
$60,000 Total Costs for one year, well justified requests for support of up to $100,000 Total Costs per
year will be considered.

International institutions and organizations are eligible for support.

Applications are due Tuesday, May 1st, 2007 for September start dates.

Applicants may request up to $60,000 (direct + indirect costs) Total Costs for one year or well justified requests for support of up to $100,000. A
narrative justification should be provided only for any major equipment (cost greater than $5,000) deemed to be necessary for the proposed project.
The number of awards will depend upon the number, quality, duration, and cost of the applications received.

Awards will be made as subcontracts from the DiaComp Coordinating and Bioinformatics Unit (CBU) at Augusta University and not directly by the
NIH. Funded awards are not allowed to submit a competitive renewal application and unfunded applications are not allowed to revise and resubmit an amended
application. Multi-year funding requests are not allowed.

Each application will receive a primary review by multiple external referees and be given scores for Significance, Investigator,
Innovation, Approach, Environment and an Overall Score based on the
NIH Scoring System for Research Applications. Scores will range from 1 to 9, where a score of 1-3 indicates an application addressing
a problem of high importance/interest in the field and may have some or no weaknesses. A score of 4-6 may be addressing a problem of high
importance in the field, but weaknesses in the criteria bring down the overall impact to medium. A score of 7-9 may be addressing a problem
of moderate/high importance in the field, but weaknesses in the criteria bring down the overall impact to low. A score of 9 indicates an
application with serious and substantive weaknesses with very few strengths. A score of 5 is considered an average score. The entire scale
(1-9) should always be considered. Please note that the Overall Score is NOT an average of the other scores.
Reviewers will strongly consider the goal of the program to support discovery (hypothesis generating) and innovative (high-risk/high-reward)
research. The DiaComp External Evaluation Committee (EEC) will provide a secondary review of all applications. Applications that are
incomplete, non-compliant and/or nonresponsive will not be reviewed. No additional materials may be submitted after the receipt date.
Scientists from the applicant institution are in conflict and excluded from review. Written comments will be provided for all reviewed
applications. Final funding decisions will be made by the NIH. All decisions are final and appeals will not be accepted for applications
submitted in response to this solicitation. Funded awards are not allowed to submit a competitive renewal application and unfunded
applications are not allowed to revise and resubmit an amended application. Multi-year funding requests are not allowed.

The application is the standard PHS 398 form including face, abstract, detailed budget,
biographical and other support pages (up to 4 pages), and research plan. The research plan (Sections A-D are limited to 5 pages) should include the following sections:

Eligible Project Directors/Principal Investigators:
Individuals with the skills, knowledge, and resources necessary to carry out the proposed research
are invited to work with their institution to develop an application for support. Individuals from
underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged
to apply for NIH support. New investigators are encouraged to apply,
but they must have a full-time faculty position or an equivalent position at non-academic institutions. Lower priority
will be given to applicants who have received DiaComp support in the past three years..

Eligible Organizations:
Higher Education Institutions

Public/State Controlled Institution of Higher Education

Private Institution of Higher Education
The following types of Higher Education Institutions are encouraged to apply for support as Public or Private Institutions of Higher Education:

When appropriate, the use of human samples is strongly encouraged, including the linking of human samples to existing tissue repositories and databases (e.g. the
NIDDK repository [www.niddkrepository.org/home/] or dkNET [http://www.dknet.org/]). Research involving human subjects is limited to observational/non-interventional studies with non-invasive or minimally invasive
testing and must have IRB approval that includes the collection and use of human samples for research purposes. Clinical trials, as defined by the NIH, are beyond the scope
of this program. For further details and resources to help clarify the NIH definition, please consult information posted at the NIH Clinical Trials website
(https://grants.nih.gov/policy/clinical-trials/definition.htm)

A summary of progress of funded projects is due two months following the completion
of the funding period.

DiaComp awardees must follow NIH and HHS policies regarding the sharing of data and resources with the scientific community
(http://grants.nih.gov/grants/sharing.htm) and agree to submit to the
DiaComp web portal all data and resources resulting from the execution of the awarded application. Data and resources may
include, but are not limited to:

histology images,

protocols,

experimental data,

RNAseq, and

progress report(s).

All data and resources generated with DiaComp support will be made immediately available to "active" DiaComp awardees (see below) and publicly available on the
DiaComp website: (1) at the time of first publication, or (2) two years from the date of data upload to the DiaComp website (
www.diacomp.org). Under certain circumstances, investigators may request an exception to the DiaComp two year public release policy by
contacting NIH Program staff and requesting a waiver. Such requests will be reviewed on a case-by-case basis and waivers will be granted only with
sufficient and compelling prior justification.

DiaComp awardees are considered "active" and granted full access to the DiaComp website as members of the DiaComp "Steering Committee" for the duration of their funding period
plus 4 years. Outgoing awardees may request an extension from NIH Program staff beyond this "active" period.

Financial acknowledgment of award: Please acknowledge all posters, manuscripts or scientific materials that were generated in part or whole
using funds from the Diabetic Complications Consortium (DiaComp) using the following
text: 'Financial support for this work provided by the NIDDK Diabetic Complications Consortium (RRID:SCR_001415,
www.diacomp.org), grants DK076169 and DK115255'.

For presentations and slides, please use the PowerPoint slide with the funding source logo found in the zip file here -
http://diacomp.org/images/diacomp-logos.zip - to
indicate that DiaComp is a funding source for your presentation.